Selective inhibitors to improve CPT-11 therapy

选择性抑制剂改善 CPT-11 治疗

基本信息

批准号：
8458610
负责人：
PHILIP M POTTER
金额：
$ 29.55万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8458610
关键词：
Acetylcholinesterase Adult Adverse drug effect Affinity Animal Model Animals Antineoplastic Agents Bile fluid Biochemical Biochemistry Biological Butyrylcholinesterase Camptothecin Carboxylic Ester Hydrolases Cell Culture Techniques Child Cholesterol Esters Cocaine Colon Carcinoma Complex Mixtures Crystallography Development Diarrhea Dose Dose-Limiting Engineering Enzyme Inhibition Enzymes Evaluation Goals Half-Life Heroin Hour Human Hydrolysis In Vitro Incidence Intestines Knock-in Mouse Lipids Liver Malignant Childhood Neoplasm Malignant Neoplasms Meperidine Metabolism Methods Modeling Mus Pediatric Neoplasm Pharmaceutical Chemistry Pharmaceutical Preparations Plant Resins Plasma Poison Procaine Prodrugs Property Proteins Quantitative Structure-Activity Relationship Reagent Resistance Ritalin SN-38 Severities Small Intestines Street Drugs Testing Therapeutic Toxic effect Type I DNA Topoisomerases Water Xenograft procedure abstracting analog antitumor agent base benzil cancer therapy carboxylesterase chemotherapeutic agent design esterase improved in vivo inhibitor/antagonist mouse model novel research study response small molecule tumor

项目摘要

Abstract CPT-11 is a highly effective, camptothecin-based anticancer agent that is currently approved for the treatment of colon cancer. This compound is a prodrug and is activated by carboxylesterases to yield SN-38, a potent topoisomerase I poison. The dose limiting toxicity for CPT-11 is delayed diarrhea that occurs 48-96 hours following administration. This is thought to arise, in part, from direct activation of CPT-11, that is secreted in the bile, by a human intestinal carboxylesterase (CE) that is highly expressed in the small intestine. We hypothesize that by inhibiting this enzyme, reduced SN-38 will be produced from drug hydrolysis in the gut, thereby reducing the toxicity associated with CPT-11 treatment. The goals of this application are therefore to develop selective CE inhibitors that can be used to ameliorate the toxicity associated with CPT-11 administration. Highly potent, non-toxic small molecule inhibitors based upon the prototypical compound benzil have been identified, and we propose to develop these agents for use in inhibition of the human intestinal CE (hiCE). NMR, x-ray crystallography, medicinal chemistry, QSAR, biochemical and in vivo approaches will all be employed to validate the efficacy of suitable compounds The specific aims of this application are: 1) to determine the mechanism of CE inhibition by benzil; 2) to develop water-soluble analogues of benzil; 3) to assess the biochemical and biological properties of these compounds; and 4) assess their efficacy at modulating CPT-11-induced toxicity in a plasma esterase-deficient mouse model where hiCE is expressed in the mouse intestine. We believe that, if successful, these studies will provide reagents that can ameliorate the delayed diarrhea associated with CPT-11 administration, and potentially allow dose intensification of the drug. This would likely result in improved antitumor efficacy and furthermore, may also allow use of this CPT-11 against more resistant malignancies that demonstrate marginal response to this agent.

抽象的 CPT-11是一种高效的基于camptothecin的抗癌药，目前已批准用于治疗结肠癌。该化合物是前药，被羧酸酯酶激活以产生SN-38，这是一种有效的拓扑异构酶I毒药。 CPT-11的剂量限制毒性是延迟的腹泻，发生48-96小时执行后。这被认为是由于CPT-11的直接激活而产生的胆汁，由人类肠道羧酸酯酶（CE）高度表达在小肠中。我们假设通过抑制这种酶，将通过肠道中的药物水解产生降低的SN-38，从而降低与CPT-11治疗相关的毒性。因此，此应用的目标是开发可用于改善与CPT-11相关的毒性的选择性CE抑制剂行政。基于原型化合物奔驰的高效，无毒的小分子抑制剂已经被确定了，我们建议开发这些药物以抑制人类肠道CE （Hice）。 NMR，X射线晶体学，药物化学，QSAR，生化和体内方法都将是用于验证合适化合物的功效本应用的具体目的是：1）确定苯甲抑制CE的机理； 2）到发展苯兹尔的水溶性类似物； 3）评估这些的生化和生物学特性化合物； 4）评估其在调节CPT-11诱导的血浆酯酶缺陷型毒性方面的功效小鼠模型，其中hice在小鼠肠中表达。我们认为，如果成功，这些研究将提供可以改善延迟腹泻的试剂与CPT-11给药相关，并有可能允许药物加强剂量。这很可能导致抗肿瘤功效的提高，此外，还可以使用此CPT-11来使用更多抗性恶性肿瘤表明对该药物的边际反应。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modulation of esterified drug metabolism by tanshinones from Salvia miltiorrhiza ("Danshen").

DOI：
10.1021/np300628a
发表时间：
2013-01-25
期刊：
Journal of natural products
影响因子：
5.1
作者：
Hatfield MJ;Tsurkan LG;Hyatt JL;Edwards CC;Lemoff A;Jeffries C;Yan B;Potter PM
通讯作者：
Potter PM

Carboxylesterase inhibitors.

DOI：
10.1517/13543776.2011.586339
发表时间：
2011-08
期刊：
Expert opinion on therapeutic patents
影响因子：
6.6
作者：
Hatfield MJ;Potter PM
通讯作者：
Potter PM

Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance.

DOI：
10.1208/s12248-016-9962-6
发表时间：
2016-11
期刊：
The AAPS journal
影响因子：
0
作者：
Argikar UA;Potter PM;Hutzler JM;Marathe PH
通讯作者：
Marathe PH

Structure-activity relationships of substituted 1-pyridyl-2-phenyl-1,2-ethanediones: potent, selective carboxylesterase inhibitors.

DOI：
10.1021/jm101101q
发表时间：
2010-12-23
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Young BM;Hyatt JL;Bouck DC;Chen T;Hanumesh P;Price J;Boyd VA;Potter PM;Webb TR
通讯作者：
Webb TR

In Silico Design and Evaluation of Carboxylesterase Inhibitors.